Infection with respiratory viruses, such as with influenza, coronavirus, and others, results in considerable pulmonary immunopathology, a large component of which results from the host specific immune responses,. Type 1 interferons (IFN-a(3) represent an important component of the innate immune response to most virus infections, and most strains of virus, including the highly pathogenic strains of influenza, have evolved mechanisms to suppress or evade these defenses. In addition to the direct inhibition of viral replication, type 1 interferons possess a variety of other immunomodulatory properties. Recently, however, it has become apparent that lung injury which occurs in the context of the T cell response to experimental influenza infection is considerably more severe in the absence of the IFN-a(3 receptor, and this is not a result of enhanced viral replication. Our data indicate that expression of the inhibitory NKG2A receptor on CD8+ T cells, which is usually induced during the course of viral clearance, is not significantly induced in the absence of the IFN-a3-receptor. Furthermore, the activation threshold of CD8+ T cells is increased by NKG2A activity, and when NKG2A binding to its cognate receptor is blocked, enhanced T cell effector activity is observed. Examination of the requirements for induction of inhibitory NKG2A expression by CD8+ T cells in influenza infection suggests that initial antigen recognition in the presence of IFN-a(3 in the regional lymph node is probably required, though expression is not observed until the cells reach the effector site in the periphery (i.e. the lung parenchyma). In order to understand the role of type 1 interferons on the inhibition of pulmonary immunopathology in respiratory virus infection, we will test the hypothesis that initial antigen engagement in the presence of type 1 interferon results in """"""""priming"""""""" for CD8+ T cell inhibitory NKG2A expression, but that actual receptor expression on CD8+ T cells requires antigen recognition in the lung parenchyma, probably on professional antigen-presenting cells such as dendritic cells. Specifically we propose to analyze the direct and indirect effects of type I interferon on regulation of CD8+ T cell NKG2A expression and immunopathologic potential, and to understand the mechanisms of regulation of CD8+ T cell NKG2A expression by IFN-a(3. This will shed important light into the mechanisms of fine-tuning of the antiviral adaptive immune responses to optimize virus clearance and minimize tissue damage which may occur in the process.

Public Health Relevance

Influenza infection results in considerable damage to infected tissues, and this becomes of paramount importance with infection of the lower respiratory tract, i.e. pneumonia, which is common with highly pathogenic strains. Understanding the fine regulation of antiviral immune responses and the ways in which these responses cause or limit lung injury will be of enormous benefit in designing rational therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI083024-05
Application #
8474687
Study Section
Special Emphasis Panel (ZAI1-BDP-I)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$426,990
Indirect Cost
$113,464
Name
University of Virginia
Department
Type
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Labonte, Adam C; Sung, Sun-Sang J; Jennelle, Lucas T et al. (2017) Expression of scavenger receptor-AI promotes alternative activation of murine macrophages to limit hepatic inflammation and fibrosis. Hepatology 65:32-43
Sung, Sun-Sang J; Li, Li; Huang, Liping et al. (2017) Proximal Tubule CD73 Is Critical in Renal Ischemia-Reperfusion Injury Protection. J Am Soc Nephrol 28:888-902
Krueger, Peter D; Narayanan, Sowmya; Surette, Fionna A et al. (2017) Murine liver-resident group 1 innate lymphoid cells regulate optimal priming of anti-viral CD8+ T cells. J Leukoc Biol 101:329-338
Sung, Sun-Sang J; Ge, Yan; Dai, Chao et al. (2017) Dependence of Glomerulonephritis Induction on Novel Intraglomerular Alternatively Activated Bone Marrow-Derived Macrophages and Mac-1 and PD-L1 in Lupus-Prone NZM2328 Mice. J Immunol 198:2589-2601
Jiang, Li; Yao, Shuyu; Huang, Su et al. (2016) Type I IFN signaling facilitates the development of IL-10-producing effector CD8+ T cells during murine influenza virus infection. Eur J Immunol 46:2778-2788
Jennelle, Lucas T; Dandekar, Aditya P; Magoro, Tshifhiwa et al. (2016) Immunometabolic Signaling Pathways Contribute to Macrophage and Dendritic Cell Function. Crit Rev Immunol 36:379-394
Teoh, Jeffrey J; Gamache, Awndre E; Gillespie, Alyssa L et al. (2016) Acute Virus Control Mediated by Licensed NK Cells Sets Primary CD8+ T Cell Dependence on CD27 Costimulation. J Immunol 197:4360-4370
Tosello-Trampont, Annie-Carole; Krueger, Peter; Narayanan, Sowmya et al. (2016) NKp46(+) natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice. Hepatology 63:799-812
DeBerge, Matthew P; Ely, Kenneth H; Wright, Peter F et al. (2015) Shedding of TNF receptor 2 by effector CD8? T cells by ADAM17 is important for regulating TNF-? availability during influenza infection. J Leukoc Biol 98:423-34
Krueger, Peter D; Kim, Taeg S; Sung, Sun-Sang J et al. (2015) Liver-resident CD103+ dendritic cells prime antiviral CD8+ T cells in situ. J Immunol 194:3213-22

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